Spinal and vagal innervation of the gastrointestinal tract. Upper portion: sensory information from vagal receptors is carried by vagal afferent nerves (1) with nerve cell bodies in the nodose ganglion to the sensory nucleus of the solitary tract (NTS). Second-order neurons transmit the information either to higher centers in the CNS (3) or via efferent vagal fibers (2) in the form of vagovagal reflexes back to the ENS. Lower portion: sensory information from spinal receptors located in the mucosa, muscle, or serosa is carried by spinal afferent fibers (4) with nerve cell bodies in the dorsal root ganglion to second-order neurons in the spinal cord. Second-order neurons transmit the information either to the CNS (6) or via sympathetic nerves (7) to prevertebral ganglia, to the ENS, and to the gastrointestinal muscle (spinal reflex). Collaterals of spinal afferents also form short reflex loops with postganglionic sympathetic nerves in the prevertebral ganglion (8). In addition to spinal afferents, sensory structures with nerve cell bodies are also located within the intestinal wall (9, 10). CM circular muscle layer, MP myenteric plexus, LM longitudinal muscle layer  (Modified from Mayer EA, Raybould HE. Role of visceral afferent mechanisms in functional bowel disorders. Gastroenterology. 1990;99(6):1688–704, with permission)
Cranial Vagal Innervation
Cranial vagal innervation is provided by the vagus nerves which innervate the esophagus, stomach, small intestine, cecum, and proximal colon. Sensory afferent neurons predominate numerically in the vagus nerve. Cell bodies are located in nodose ganglion, and the central processes terminate in the nucleus of the solitary tract (NTS). Vagal afferents are believed as mainly mediating physiological rather than harmful sensations, transmitting information on nature and composition of the intestinal content and motility and contractile tension of the smooth muscle.
Visceral afferents running in the spinal cord are referred as “spinal afferents ” when the term “sympathetic innervation ” is restricted to spinal efferent innervation . Spinal innervation is provided by greater splanchnic nerve which forms three main ganglia from which they distribute to the viscera: the celiac ganglion distributes nerves to the esophagus, stomach, and duodenum; the superior mesenteric ganglion distributes nerves to the intestines down to the ascending colon and the inferior mesenteric ganglion to the colon from the hepatic flexure to the rectum. Sensory afferent neurons account for 10–20 % of fibers in spinal afferents, and cell bodies are located in dorsal root ganglia (DRG) at the cervical, thoracic, and upper lumbar spine . Their central processes terminate in the dorsal horn of the spinal cord. Spinal afferents transmit information on potentially noxious mechanical or chemical stimuli and are involved in sensation of visceral pain . However, it should be kept in mind that, in the CNS, vagal inputs likely integrate with the inputs from the spinal pathways, and therefore, perception of pain is the result of modulation of vagal and spinal inputs . Vagal and spinal afferents are predominantly unmyelinated C-fibers or thinly myelinated A-delta fibers with low conduction velocity.
The distal third of the colon is innervated by pelvic nerves and pudendal nerves. This area of the GI tract receives dual spinal innervation from splanchnic and pelvic afferents . Pelvic spinal afferents connects to the periphery through parasympathetic nerves innervating the pelvic organs. Cell bodies are located in the DRG.
At the level of the gastrointestinal tract, sensory neurons and enteroendocrine cells serve as transducers. Vagal mechanoreceptors are located in the mucosa or muscle layer, and spinal receptors are located in the mucosa, muscle, or serosa . Gut sensory terminals and receptors include mechanoreceptors, chemoreceptors, thermoreceptors, and nociceptors . Recently most evidence points toward polymodality of the visceral receptors.
Vagal sensory endings terminate in the intestinal wall according to different possibilities . “Intramuscular arrays” are located within the circular or longitudinal muscle layers and appear to be stretch receptors. “Intraganglionic endings” (IGLE) are situated at the surface of myenteric ganglia and are activated by tension of the gut wall. They are supposed to transmit signals that are perceived as nonpainful sensation of fullness. Mucosal projections extend into the lamina propria and correspond to mucosal receptors .
Spinal terminals are less well characterized and are anatomically not clearly identifiable. Studies have shown that mechanonociceptors mediating transduction of pain evoked after high amplitude distension are spinal afferents . Fine “varicose branching axons” that appear as specialized endings can be demonstrated in the serosa and mesenteries around blood vessels . Knowledge on mechanotransduction has been recently reviewed .
Endoderm-derived enteroendocrine cells are contained in the intestinal mucosa throughout the GI tract behind the esophagogastric junction and provide an interface between external milieu and terminal endings of afferents. They resemble sensory cells in the lingual epithelium taste buds. They have an apical tuft of microvilli exposed to the luminal content and release bioactive molecules (serotonin (5HT)—synthetized by enterochromaffin (EC) cells—and hormones such as CCK, leptin, orexin, ghrelin) that stimulate afferent terminal in the lamina propria in response to appropriate stimuli. Enteroendocrine cells are involved in chemosensitivity and respond to nutrients playing a key role in the glucose homeostasis . It has also been shown that the gut is able to “taste” odorants, spices, and bitter taste via enteroendocrine cells . EC cells contain 5HT that is known to be released in response to endogenous chemical stimuli  and exogenous dietary amines, tastants, or microbiota-derived metabolites (e.g., short-chain fatty acids) . They play a key role in the gut mechanosensitivity in response to mucosal deformation: by acting on 5HT3 receptors, 5HT release is involved in the peristaltic reflex by activating intrinsic neurons (IPAN) and in visceral sensations by activating mucosal endings of sensory afferents.
Receptors on Visceral Afferents Involved in Visceral Pain
A large number of bioactive substances and chemical mediators have been implicated in the sensory signal transduction of visceral pain. These substances produce their effects by three distinct processes: (1) direct activation of a receptor, which generally involves the opening of ion channels; (2) sensitization, which results in afferent hyperexcitability; and (3) through genetic change that alters the phenotype of the afferent nerve (alterations in the expression or activity of channels and receptors). Figure 4.2 depicts the complexity of receptors and bioactive substances involved in visceral sensitivity in terminal afferents.
Some of the potential receptor mechanisms underlying activation (depolarization) and sensitization at the terminal of a gastrointestinal sensory afferent [140, 141]. Separate mechanisms underlie activation and sensitization. Some mediators such as serotonin (5HT) cause activation via 5HT3 receptors, whereas others like PGE2 acting at EP2 receptors sensitize visceral afferent responses to other stimuli. Still others, for example, adenosine (Adeno), cause both stimulation and sensitization, possibly through distinct receptor mechanisms. Bradykinin (BK) has a self-sensitizing action, stimulating discharge through activation of phospholipase C (PLC) and enhancing excitability via prostaglandins (PGs) after activation of phospholipase A2 (PLA2). Inflammatory mediators can be released from different cell types (e.g., sympathetic varicosities, mast cells, lymphocytes, and blood vessels) present in or around the afferent nerve terminal. 5HT, ATP, H+, and capsaicin (Cap) can directly activate cation channels such as TRPA1 , TRPV1 [90, 91, 142],_ENREF_9 P2X , TRPV4 [97, 98], and ASIC [90, 91]. Adenosine, histamine, prostaglandins (not PGE2), and proteases such as mast cell tryptase (Tryp) and thrombin (Thro) act on G protein-coupled receptors (PAR-2  and PAR-4 ) leading to a calcium-dependent modulation of ion channel activity. TRPV4 is co-localized with PAR-2 and mainly in colonic sensory neurons with an important interaction in visceral hypersensitivity. Cannabinoids produce peripheral analgesic effect by activation of TRPA1 and indirect activation of TRPV1 . Sensitization, however, may be mediated by increased intracellular cAMP. Adenosine and PGE2 can generate cAMP directly through G protein-coupled stimulation of adenylate cyclase (AC). In contrast, histamine (Hist) may act indirectly through the generation of prostaglandins. The actions of cAMP downstream are currently unknown but may involve modulation of ion channels, interaction with other second messengers (e.g., calcium), or even changes in receptor expression. AA, arachidonic acid; ASIC, acid-sensing ion channels; COX-1 and COX-2, cyclooxygenase-1 and cyclooxygenase-2; DAG, diacylglycerol; IP3, inositol 1,4,5-trisphosphate; PARs, protease-activated receptors; TRPA1, transient receptor potential cation channel A1; TRPV1 and TRPV4, transient receptor potential cation channel subfamily V member 1 and 4  (Modified from Kirkup AJ, Brunsden AM, Grundy D. Receptors and transmission in the brain-gut axis: potential for novel therapies. I. Receptors on visceral afferents. Am J Physiol Gastrointest Liver Physiol. 2001;280(5):G787–94, with permission)
Central Pathways of Visceral Sensitivity
Vagal Central Pathway
Vagal afferents project in the brainstem to the NTS which displays a viscerotopic organization . The NTS acts as a relay for the enormous amount of information arriving from abdominal viscera and, in turn, sends out a network to motor nucleus (nucleus ambiguus (NA) and dorsal motor nucleus (DMN)) providing the circuits for basic reflexes of the GI tract. NTS also projects fibers to higher centers: (1) information is relayed to parabrachial nuclei (PBN), which in turn are connected to higher brain centers (amygdala system), and (2) long projections terminate in the thalamus, hypothalamus, and anterior cingulate cortex (ACC) and insular cortical regions regulating arousal, emotional, autonomic, and behavioral responses (see below) [2, 4].
Spinal Central Pathway
After entering the spinal cord, first-order neurons synapse in the dorsal horn and second-order neurons project to the brain through a number of different tracts: spinoreticular, spinomesencephalic, spinohypothalamic (which activate unconscious reflex autonomic responses), and spinothalamic . The spinothalamic tract, the most important pathway involved in conscious sensations, is classically subdivided into lateral spinothalamic tract that mediates the sensory-discriminative aspects of pain (localization, intensity) and medial spinothalamic tract mediating the motivational-affective aspects of pain (suffering, unpleasantness). Lateral spinothalamic tract projects to the ventral posterior lateral nucleus of the sensory thalamus, from which information is relayed to the somatosensory cortex (SI and SII) and the insula cortex. The medial spinothalamic tract projects to medial dorsal and ventral medial posterior nuclei of the thalamus and mainly projects, with spinoreticular, spinomesencephalic, and spinohypothalamic tracts, onto brainstem and midbrain structures such as reticular formation, NTS, periaqueductal gray (PAG), PBN, and hypothalamus. From these structures, third-order neurons project to areas involved in emotional functioning, like anterior the anterior cingulated cortex (ACC) and the orbitomedial prefrontal cortex (PFC). Animal studies have shown that the spinal dorsal column (dorsal funiculus) seems to play also an important role in viscerosensory transmission, especially in nociceptive transmission, but evidence in humans is limited and discussed on the basis of the effectiveness of midline myelotomy in visceral pain due to cancer .
Central Processing of Visceral Sensitivity
The main function of somatosensory cortex (SI and SII) is to provide information about intensity and localization of the stimulus (sensory discriminative). The ACC mainly processes pain affect (unpleasantness, pain-related anxiety) and cognitive aspect of the pain experience (attention, anticipation). However, important interactions between these two systems are certainly present. The insula integrates internal state of the organism and encodes sensory and emotional information related to pain. The prefrontal cortex is believed to play a key role in the integration of sensory information and in affective aspect of the sensation. Furthermore, this region is also involved in the generation of and choice between autonomic and behavioral response patterns and has been shown to be a putative biological substrate of cognitive influences (including placebo effect) on emotions and the affective dimension of pain . These brain regions are actually organized and function in complex networks. Schematically, three of them, the salience network, the emotional arousal network, and the sensorimotor network, are involved in chronic visceral pain (for a review, see ).
Though a number of analytic techniques and experimental paradigms have been used, quantitative meta-analysis techniques have permitted to pool the results of 18 studies conducted between 2000 and 2010 using PET or fMRI in adult controls and adult IBS subjects undergoing supraliminal rectal distension (painful or not). Data from the healthy control subjects confirm that regions activated in response to supraliminal rectal distension include zones associated with visceral sensation (bilateral anterior insula, bilateral midcingulate cortex, and right thalamus), emotional arousal (right perigenual ACC), and regions associated with attention and modulation of arousal (left inferior parietal, left lateral, and right medial prefrontal cortex) . There is evidence that the cerebellum is also involved in nociceptive processing and that symptoms of anxiety and depression modulate cerebellar activity during visceral stimulation . Figure 4.3 summarizes the ascending pathway involved in visceral sensation after colonic stimulation.
Ascending pathway involved in nociceptive visceral sensation. Colonic stimulation activates afferent spinal terminals whose cell bodies are situated in the dorsal root ganglia. These first-order neurons project to the dorsal horn, and second-order neurons project to the brain through spinoreticular, spinomesencephalic, spinohypothalamic, and spinothalamic tracts. The first three tracts are involved in unconscious reflex behavior, whereas spinothalamic tract drives conscious visceral sensations. Third-order neurons project information to the somatosensory cortex (S1 and S2); to areas involved in emotional functioning, like anterior cingulated cortex (ACC) and the prefrontal cortex (PFC); and to the insula cortex. The spinal dorsal column (dorsal funiculus) seems to play also an important role in viscerosensory transmission, especially in nociceptive transmission
Descending Modulatory Pathways
Pain afferent stimuli reaching brain structures induce projections able to modulate ongoing transmission of those inputs at the level of the dorsal horn, thus achieving a descending modulatory control. Descending modulation can be inhibitory, facilitatory, or both [2, 14]. At the cortical level, the ACC is the key region involved in this control through projections toward the amygdala and the PAG. Thus, cognitive and affective factors may exert influence on pain transmission through the ACC. The amygdala and the PAG project in turn to the locus coeruleus, the raphe nuclei, and the rostrolateral ventral medulla, which send projections to the dorsal horn and modulate the synaptic transmission of sensory information at this level.
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Definitions applied in visceral sensitivity have been borrowed from the somatic pain field. Hypersensitivity is defined as an increased sensation of stimuli (appraised by measurement of threshold volumes or pressure for first sensation or pain). Hyperalgesia is an increased pain sensation to a certain painful stimulus and allodynia a stimulus previously not perceived as being painful that becomes painful. Visceral hypersensitivity is defined as an exaggerated perceptual response (hyperalgesia, allodynia, abnormal somatic referral) reported to peripheral events. Theoretically, visceral hypersensitivity could be the result of changes in visceral afferent signal processing (reflecting increased visceral afferent input to the brain from the gut) or be the consequence of alterations in pain modulation mechanisms (i.e., central sensitization or pain inhibition process at the level of the central nervous system), or be due to alteration of pain processing or derive from a variable combinations of these pathways.
In pediatrics, several independent groups have reported that 75–100 % of children affected by IBS have a low rectal sensory threshold for pain (i.e., visceral hypersensitivity) as compared to control children [19–23]. In adults, the prevalence of visceral hypersensitivity varies from 20 %  to 94 %  across studies suggesting that visceral hypersensitivity is a more reliable diagnostic marker in children than in adults.
Aberrant viscerosomatic projections have also been reported in children with IBS and FAP who refer, in response to rectal distension, their sensation to aberrant sites compared to the controls, i.e., with abdominal projections on dermatomes T8 to L1 wherein controls referred their sensation to the S3 dermatome. In adults and in children, visceral hypersensitivity has been shown to be “organ specific” with a low rectal sensitivity threshold in IBS patients [25–32], a low gastric sensitivity threshold in FD [33–36], and “diffuse” hypersensitivity in mixed IBS + FD patients .
Data from studies on the visceral hypersensitivity in FGID and specifically in IBS favor the heterogeneity of causes and mechanisms in a population of patients. Preclinical animal models have permitted investigations of cellular and molecular abnormalities in the gastrointestinal tract as well as in the CNS (spinal cord and brain) [38, 39]. In humans, studies have similarly found several modifications in the rectal and colonic mucosa (inflammation, mast cell infiltration, serotonin pathway anomalies) in IBS patients. On the other hand, functional brain imaging techniques have demonstrated, in adults and in adolescents, the importance of a role for CNS dysregulation of pain processing in IBS.
Inflammation and Epithelial Permeability
It is clearly accepted that IBS may be triggered by enteric bacterial infections that could have consequences on local inflammation, EC cell, and mast cell counts [40, 41]. Low-grade inflammation has been reported in the enteric ganglia  and in the mucosa [42, 43] of patients with IBS. A slight increase of fecal calprotectin is reported in children with IBS . Proinflammatory cytokine (IL-1, IL-6, and TNF-α) production by peripheral blood mononuclear cells is upregulated in patients with IBS . This suggests that inflammatory status drives possibly local modifications promoting sensitization. Stress via the hypothalamic-pituitary-adrenal (HPA) axis modulates the inflammation and the cytokine production. Increased intestinal permeability either jejunal or colonic [44, 46] with alterations of the junction protein expression [47, 48] is also associated to the minimal mucosal inflammation.
Mast Cells and Mucosal Innervation
Abnormal mast cell numbers (increase [49–51] or decrease ) and close proximity to mucosal enteric neurites has been reported in stressed rats [49, 50] and in the colon of adult [51, 52] as well as pediatric [53, 54] patients with IBS (for a review, see ). Stress-related activation of the HPA axis increases mast cell number and triggers mast cell degranulation via the corticotropin-releasing factor (CRF). Triggers of mast cell degranulation include also IgE, histamine, substance P, calcitonin-related gene peptide, nerve growth factor (NGF), and lipopolysaccharide. Current evidence suggests that activity and enhanced degranulation of mast cells rather than an increased number is predominant in the pathophysiology of visceral hypersensitivity.
CRF, released by the paraventricular nucleus of the hypothalamus, by activating CRF1 receptor either in the brain or in the colonic mucosa, plays an important role in modulating the water and ion secretion, colonic motility, and intestinal permeability via nerve-mast cell interaction as well as directly on intestinal epithelium (for a review, see ).
NGF [54, 57, 58], tryptase [59, 60], and histamine are mediators released by mast cells that activate afferent nerves and might therefore mediate the visceral hypersensitivity . NGF evokes nerve fiber growth and pain transmission by interaction with the tyrosine kinase receptor A (TrkA). Dothel et al. have shown that patients with IBS have a higher density of mucosal nerve fibers and increased nerve outgrowth in the colonic mucosa. These findings were associated with increased expression of NGF and TrkA, both expressed on the surface of mast cells . Willot et al. reported a higher NGF content in colonic biopsies from children with diarrhea-predominant IBS .
Enteric Glial Cells
Enteric glial cells (EGC ) are a major component of the enteric nervous system with an extensive network throughout the intestinal mucosa. They play an important role in the control of intestinal motility and are involved in intestinal epithelial barrier function to maintain intestinal homeostasis and in repair mechanism after mechanical or inflammatory injury. In physiological conditions, EGC can be activated by bacteria, luminal factors, or neuronal factors. EGC-derived factors such as S-nitrosoglutathione, GDNF, and TGF-β are important mediators by reducing epithelial permeability [62–64]. A recent study demonstrated the association of EGC activation and stress-induced colonic hypercontractility in an IBS-mouse model .
Serotonin (5HT) is secreted by enterochromaffin (EC) cells and plays a critical role in the regulation of GI motility, secretion, and sensation through specific receptors [66–70]. The subtypes 5HT3, 5HT4, and 5HT2B are supposed to be the main receptors involved in visceral sensitivity . 5HT synthesis and bioavailability are also under dependence of the microbiota [72, 73]. The 5HT transporter (SERT) terminates the actions of 5HT by removing it from the interstitial space [74–76]. Genetic polymorphism of SERT could influence visceral sensitivity: the short allele of the gene 5HTTLPR is associated with reduced 5HT transporter (SLC6A4) function and higher rating of rectal pain sensation and altered brain activation . Coates et al. have reported that mucosal 5HT, tryptophan hydroxylase-1 messenger RNA (TpH1, the rate-limiting enzyme in the biosynthesis of 5HT), and SERT mRNA were all significantly reduced in colonic mucosa of adult patients with IBS . In children, 5HT content was found significantly higher in the rectal mucosa of pediatric subjects with IBS as compared to controls, and SERT mRNA was significantly lower in patients than in controls . Park et al. have shown a correlation between EC cells and rectal hypersensitivity in adults suggesting that these cells play a role in visceral sensitivity .
PAR-2 and PAR-4
Protease-activated receptors (PAR) are G protein-coupled receptors that are activated after cleavage by proteases of their N-terminal domain, which releases a tethered ligand that binds and activates the receptor. PARs can be activated by mast cell tryptase, pancreatic trypsin, and exogenous proteinases . PAR-1, PAR-2, and PAR-4 are distributed throughout the GI tract. PAR-1 and PAR-2 are involved in modulation of intestinal inflammation [82, 83], and PAR-2  and PAR-4 are key players in visceral pain and hypersensitivity. Activation of PAR-2 is pronociceptive [60, 85], and PAR-4 is conversely an inhibitor of visceral hypersensitivity [86, 87]. It is conceivable that visceral hypersensitivity may result from disequilibrium between the pronociceptive effects of PAR-2 activation (or overexpression) incorrectly counterbalanced by the antinociceptive effect of PAR-4 activation (or low expression).
TRPV1, TRPV4, and TRPA1
Members of the transient receptor potential (TRP) family of ion channels are important sensors of environmental stimuli [88, 89]. TRP vanilloid 1 (TRPV1) ion channel is expressed in primary afferent neurons. A role of TRPV1 in visceral hypersensitivity is supported by several studies in rodents showing that TRPV1 mediates visceral nociception behavior [90–92]. In human adults, a potential role of TRPV1 is supported by a higher density of TRPV1 fibers in the colonic mucosa of patients with IBS as compared to controls  but not confirmed by others . Rectal application of the TRPV1-agonist capsaicin results in increased pain response in IBS patients . Sugiuar et al. have shown that TRPV1 function is enhanced by 5HT in colonic sensory neurons . Such mechanism involving histamine H1 receptors was recently demonstrated in humans . Therefore, sensitization rather than overexpression of TRPV1 is hypothesized to explain hypersensitivity. Studies have also emphasized the role of TRPV4 expression and function in visceral nociception [97–99]. TRPV4 is expressed in visceral afferent neurons  and epithelial colonic cells . TRPV4 is responsible for 5HT and histamine-induced visceral hypersensitivity  and is thought to be the mediator of PAR-2-induced colonic sensitization [97, 99].
TRPA1 is present in colonic myenteric neurons, but also in numerous non-neuronal tissues, including the colon . Cold and mechanical stimuli but also products formed during oxidative stress can activate TRPA1. Activation of TRPA1 results in mechanical hypersensitivity. Cenac et al. have evaluated levels of metabolites that activate calcium channels TRPV1, TRPV4, and TRPA1 in IBS patients. The level of the TRPV4 agonist was elevated, but not the levels of the other agonists . Figure 4.4 summarizes the complex interactions among the different factors responsible for visceral hypersensitivity involved at the peripheral level.
Pathophysiology of visceral hypersensitivity: peripheral mechanisms. Enteric infection, dysbiosis, or stressful events activate intestinal epithelium, enterochromaffin (EC) cells, enteric glial cells, mast cells, and afferent nerve terminals. Physiological events such as mucosal inflammation and increased intestinal permeability as well as CRF and epinephrine secretion elicit mast cell degranulation and EC cell stimulation which in turn secrete neurotransmitters (5HT, histamine), neurotrophins (NGF), proteases, and prostaglandins. These bioactive substances activate receptors present at the terminal end of the afferent nerves and elicit pain, sensitization, and neurite outgrowth leading to chronic changes and maintenance of chronic pain. Red: trigger events eliciting visceral hypersensitivity; green: tissues involved in visceral hypersensitivity; light blue: pathophysiological mechanisms responsible for visceral hypersensitivity; dark blue: some of the bioactive substances activating receptors at the terminal end of afferent spinal neuron. Note that some of these components may stimulate mast cell degranulation therefore creating a loop with amplification of the nerve activation. CRF corticotropin-releasing factor, NGF nerve growth factor, 5HT serotonin, EC cells enterochromaffin cells
When measured by using rectal distensions in humans, the perceptual response expressed by the subject and measured as the rectal sensory threshold can be separated into two components according to the signal detection theory [103–105]: the perceptual sensitivity (the physiological capacity of the neurosensory apparatus of the rectum to detect intraluminal distension, i.e., the ability to detect intraluminal distension) and the response bias (how the sensation is reported). The perceptual sensitivity reflects the ability of the organ to detect and transduce the stimulus to the central nervous system. The response bias is the reporting behavior (intensity, painfulness) which represents a cognitive process influenced by past experience and psychological state. Increased response bias (i.e., a tendency to report as painful visceral sensations) with a similar perceptual sensitivity than controls (i.e., same ability as controls to discriminate rectal distensions) has been reported by one group  but was not confirmed by others .
Though perceptual sensitivity can be related to peripheral mechanisms, response bias results of central modulation of the stimuli, and processing of the sensation.
Central Sensitization and Altered Brain-Gut Communication
Central sensitization is a phenomenon that has been described in chronic somatic pain [108, 109]: a peripheral injury triggers a long-lasting increase in the excitability of spinal cord neurons inducing an increase in the afferent activity secondary to profound changes in the gain of the somatosensory system. This central facilitation results in allodynia, hyperalgesia, and a receptive field expansion that enables input from non-injured tissue to produce pain (secondary hyperalgesia). In an animal model of stress-induced visceral hyperalgesia, spinal microglia activation has been shown to play a key role in facilitation of pain stimuli . In a stressful model of visceral hypersensitivity, increased colonic NGF synthesis in response to epinephrine has been shown to be responsible for the central sensitization . In humans, using RIII reflex, evidence of an alteration (facilitation) of spinal modulation of nociceptive processing has been shown in IBS . Stabell et al. investigated pain thresholds in 961 adolescents in the general population. Adolescents with IBS symptoms had lower pain thresholds with widespread hyperalgesia. The association of visceral hypersensitivity to somatic thermal hyperalgesia has also been reported by some authors in a subset of IBS adult patients [30, 113, 114]. These findings are supporting the theory of central sensitization mechanism . Alterations of pain inhibition processes in adult  as well as young girls  with IBS have also been reported.
Dysregulation of Pain Processing
Functional cerebral imaging techniques have led to significant progress in the understanding of cortical and subcortical processing of pain in IBS. The results of the previously cited meta-analysis of 18 studies performed in adult controls and IBS subjects undergoing supraliminal rectal distension (painful or not) support a role for CNS dysregulation of pain processing in IBS . Visceral pain processing is a complex process and results from interactions of brain areas operating in networks (the salience network, the emotional arousal network, and the sensorimotor network). Structural and functional alterations in those brain regions as well as prefrontal regions are the most consistently reported findings in adult IBS as compared to controls . A recent study in adolescent patients with IBS demonstrated also a greater extent and magnitude of activation to rectal distension than healthy controls in a number of key areas of the salience network, especially the cingulate and insular cortices that are involved in visceral afferent and emotional arousal processing .
Other Potential Mechanisms
Other neuromediators involved in visceral sensation that have been studied as potential peripheral or central mechanisms of visceral hypersensitivity are listed below. Some of them are (or have been) actively studied as possible targets for treatments of FGID.
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